Shock wave lithotripsy (SWL) has proven to be very effective treatment for the elimination of upper urinary tract stone. Although SWL is widely regarded as effective and safe there is growing concern that lithotripsy also poses a health risk. It is now well documented that SWL causes trauma to the kidney, dominated by vascular injury, and that the acute damage caused by shock wave treatment can lead to serious long-term complications in some individuals )e.g.new onset hypertension in the elderly). Thus, the safety of SWL is in question. It is feasible to improve SWL, to change the properties of lithotripter shock waves and/or derive new patient protocols to make treatment safer and more effective. However, basic information is missing that would allow such improvements to be made: how lithotripter schock waves cause tissue damage is unknown; the physical mechanisms responsible for kidney damage in SWL have yet to be determined. The objective of this project is to determine the physical mechanisms of tissue damage in SWL. We propose a biophysics- based in vitro approach to test the hypothesis that kidney damage in SWL is due to two prominent features of lithotripter shock waves: acoustic cavitation and shear stress. This revised proposal has four Specific Aims 1 and 2 have undergone extensive revisions in response to reviewers' commetns. Aim 1 will use isolated kidneys to characterize vascular trauma due to cavitation, determine if mechanical forces other than cavitation contribute to tissue damage, and will test the idea that kidney damage in SWL can be inhibited by administering SW's when the kidney is under increased hydrostatic pressure (to suppress cavitation detection and quantitation to characterize the inception and propagation of cavitation in blood, and test the idea that vascular damage is dependent upon a shock wave- induced reduction in the rate of renal blood flow. We will assess the potential for the vasculature to support cavitation and determine how cavitation is affected by vessel size. In Aim 3 we will use cultured cell models to determine if cavitation is responsible for damage to renal tubules, and in Aim 4 we will determine how shear stress contributes to SWL cell injury. The main goal of this project is to determine the physical mechanisms that are responsible for tissue damage in SWL, so that strategies can be developed to make SWL safer, to reduce or eliminate the significant acute schock wave-induced renal trauma that leads to irreversible kidney damage.